Journal Article

PUBDB-2015-02248

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Targeting DnaN for tuberculosis therapy using novel griselimycins

Kling, A. ; Lukat, P.>Extern* ; Almeida, D. V. ; Bauer, A. ; Fontaine, E. ; Sordello, S. ; Zaburannyi, N. ; Herrmann, J. ; Wenzel, S. C. ; Konig, C. ; Ammerman, N. C. ; Barrio, M. B. ; Borchers, K. ; Bordon-Pallier, F. ; Bronstrup, M. ; Courtemanche, G. ; Gerlitz, M. ; Geslin, M. ; Hammann, P. ; Heinz, D. W. ; Hoffmann, H. ; Klieber, S. ; Kohlmann, M. ; Kurz, M. ; Lair, C. ; Matter, H. ; Nuermberger, E. ; Tyagi, S. ; Fraisse, L. ; Grosset, J. H. ; Lagrange, S. ; Muller, R. (Corresponding author)

2015
American Association for the Advancement of Science16205 Washington, DC [u.a.]

This record in other databases:        

Please use a persistent id in citations: doi:10.1126/science.aaa4690

Abstract: The discovery of Streptomyces-produced streptomycin founded the age of tuberculosis therapy. Despite the subsequent development of a curative regimen for this disease, tuberculosis remains a worldwide problem, and the emergence of multidrug-resistant Mycobacterium tuberculosis has prioritized the need for new drugs. Here we show that new optimized derivatives from Streptomyces-derived griselimycin are highly active against M. tuberculosis, both in vitro and in vivo, by inhibiting the DNA polymerase sliding clamp DnaN. We discovered that resistance to griselimycins, occurring at very low frequency, is associated with amplification of a chromosomal segment containing dnaN, as well as the ori site. Our results demonstrate that griselimycins have high translational potential for tuberculosis treatment, validate DnaN as an antimicrobial target, and capture the process of antibiotic pressure-induced gene amplification.

Note: (c) AAAS. Post referee full text in progress. Embargo for full text 6 months from 06.06.15.

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Contributing Institute(s):

1. DOOR-User (DOOR)

Research Program(s):

1. 6G3 - PETRA III (POF3-622) (POF3-622)

Experiment(s):

1. PETRA Beamline P11 (PETRA III)

Appears in the scientific report 2015

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Database coverage:
; BIOSIS Previews ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; IF >= 30 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection ; Zoological Record

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